Tafasitamab

MONJUVI, in combination with lenalidomide, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). MONJUVI is a CD19-directed cytolytic antibody indicated in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

For injection: 200 mg of tafasitamab-cxix as white to slightly yellowish lyophilized powder in single-dose vial for reconstitution and further dilution. For injection: 200 mg of tafasitamab-cxix as lyophilized powder in single-dose vial for reconstitution.( 3 )

None. None.

Infusion-Related Reactions : Monitor patients frequently during infusion. Interrupt or discontinue infusion based on severity. ( 2.3 , 5.1 ) Myelosuppression : Monitor complete blood counts. Manage using dose modifications and growth factor support. Interrupt or discontinue MONJUVI based on severity. ( 2.3 , 5.2 ) Infections : Bacterial, fungal and viral infections can occur during and following MONJUVI. Monitor patients for infections. ( 2.3 , 5.3 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.4 )

5.1 Infusion-Related Reactions MONJUVI can cause infusion-related reactions [see Adverse Reactions (6.1) ] . In L-MIND, infusion-related reactions occurred in 6% of the 81 patients. Eighty percent of infusion-related reactions occurred during cycle 1 or 2. Signs and symptoms included fever, chills, rash, flushing, dyspnea, and hypertension. These reactions were managed with temporary interruption of the infusion and/or with supportive medication. Premedicate patients prior to starting MONJUVI infusion [see Dosage and Administration (2.2) ] . Monitor patients frequently during infusion. Based on the severity of the infusion-related reaction, interrupt or discontinue MONJUVI [ see Dosage and Administration (2.3) ] . Institute appropriate medical management.

5.2 Myelosuppression MONJUVI can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1) ] . In L-MIND, Grade 3 neutropenia occurred in 25% of patients, thrombocytopenia in 12%, and anemia in 7%. Grade 4 neutropenia occurred in 25% and thrombocytopenia in 6%. Neutropenia led to treatment discontinuation in 3.7% of patients. Monitor CBC prior to administration of each treatment cycle and throughout treatment. Monitor patients with neutropenia for signs of infection. Consider granulocyte colony-stimulating factor administration. Withhold MONJUVI based on the severity of the adverse reaction [see Dosage and Administration (2.3) ]. Refer to the lenalidomide prescribing information for dosage modifications.

5.3 Infections Fatal and serious infections, including opportunistic infections, occurred in patients during treatment with MONJUVI and following the last dose [see Adverse Reactions (6.1) ]. In L-MIND, 73% of the 81 patients developed an infection. The most frequent infections were respiratory tract infection (24%), urinary tract infection (17%), bronchitis (16%), nasopharyngitis (10%) and pneumonia (10%). Grade 3 or higher infection occurred in 30% of the 81 patients. The most frequent grade 3 or higher infection was pneumonia (7%). Infection-related deaths were reported in 2.5% of the 81 patients. Monitor patients for signs and symptoms of infection and manage infections as appropriate.

5.4 Embryo-Fetal Toxicity Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . MONJUVI is initially administered in combination with lenalidomide. The combination of MONJUVI with lenalidomide is contraindicated in pregnant women because lenalidomide can cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-related reactions [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Infections [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥20%) are neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact MORPHOSYS US INC. at 1-844-667-1992 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Diffuse Large B-Cell Lymphoma The safety of MONJUVI was evaluated in L-MIND [see Clinical Studies (14) ]. Patients (n=81) received MONJUVI 12 mg/kg intravenously in combination with lenalidomide for a maximum of 12 cycles, followed by MONJUVI as monotherapy until disease progression or unacceptable toxicity as follows: Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle; Cycles 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle; Cycles 4 and beyond: Days 1 and 15 of each 28-day cycle. Among patients who received MONJUVI, 57% were exposed for 6 months or longer, 42% were exposed for greater than one year, and 24% were exposed for greater than two years. Serious adverse reactions occurred in 52% of patients who received MONJUVI. Serious adverse reactions in ≥6% of patients included infections (26%), including pneumonia (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 5% of patients who received MONJUVI, including cerebrovascular accident (1.2%), respiratory failure (1.2%), progressive multifocal leukoencephalopathy (1.2%) and sudden death (1.2%). Permanent discontinuation of MONJUVI or lenalidomide due to an adverse reaction occurred in 25% of patients and permanent discontinuation of MONJUVI due to an adverse reaction occurred in 15%. The most frequent adverse reactions which resulted in permanent discontinuation of MONJUVI were infections (5%), nervous system disorders (2.5%), respiratory, thoracic and mediastinal disorders (2.5%). Dosage interruptions of MONJUVI or lenalidomide due to an adverse reaction occurred in 69% of patients and dosage interruption of MONJUVI due to an adverse reaction occurred in 65%. The most frequent adverse reactions which required a dosage interruption of MONJUVI were blood and lymphatic system disorders (41%), and infections (27%). The most common adverse reactions (≥ 20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite. Table 3 summarizes the adverse reactions in L-MIND. Table 3: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Received MONJUVI in L-MIND Adverse Reaction MONJUVI (N=81) All Grades (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Neutropenia 51 49 Anemia 36 7 Thrombocytopenia 31 17 Febrile neutropenia 12 12 General disorders and administration site conditions Fatigue Fatigue includes asthenia and fatigue 38

3.7 Pyrexia 24

1.2 Peripheral edema 24 0 Gastrointestinal disorders Diarrhea 36

1.2 Constipation 17 0 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain lower, and abdominal pain upper 15

1.2 Nausea 15 0 Vomiting 15 0 Respiratory, thoracic and mediastinal disorders Cough 26

1.2 Dyspnea 12

1.2 Infections Respiratory tract infection Respiratory tract infection includes: lower respiratory tract infection, upper respiratory tract infection, respiratory tract infection 24

4.9 Urinary tract infection Urinary tract infection includes: urinary tract infection, Escherichia urinary tract infection, urinary tract infection bacterial, urinary tract infection enterococcal 17

4.9 Bronchitis 16

1.2 Metabolism and nutrition disorders Decreased appetite 22 0 Hypokalemia 19 6 Musculoskeletal and connective tissue disorders Back pain 19

2.5 Muscle spasms 15 0 Skin and subcutaneous tissue disorders Rash Rash includes rash, rash maculo-papular, rash pruritic, rash erythematous , rash pustular 15

2.5 Pruritus 10

1.2 Clinically relevant adverse reactions in <10% of patients who received MONJUVI were: Blood and lymphatic system disorders : lymphopenia (6%) General disorders and administration site conditions : infusion-related reaction (6%) Infections : sepsis (4.9%) Investigations : weight decreased (4.9%) Musculoskeletal and connective tissue disorders : arthralgia (9%), pain in extremity (9%), musculoskeletal pain (2.5%) Neoplasms benign, malignant and unspecified : basal cell carcinoma (1.2%) Nervous system disorders: headache (9%), paresthesia (7%), dysgeusia (6%) Respiratory, thoracic and mediastinal disorders: nasal congestion (4.9%), exacerbation of chronic obstructive pulmonary disease (1.2%) Skin and subcutaneous tissue disorders: erythema (4.9%), alopecia (2.5%), hyperhidrosis (2.5%) Table 4 summarizes the laboratory abnormalities in L-MIND. Table 4: Select Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Received MONJUVI in L-MIND Laboratory Abnormality MONJUVI The denominator used to calculate the rate was 74 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Chemistry Glucose increased 49 5 Calcium decreased 47

1.4 Gamma glutamyl transferase increased 34 5 Albumin decreased 26 0 Magnesium decreased 22 0 Urate increased 20 7 Phosphate decreased 20 5 Creatinine increased 20

1.4 Aspartate aminotransferase increased 20 0 Coagulation Activated partial thromboplastin time increased 46 4.1

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other tafasitamab products may be misleading. Overall, no treatment-emergent or treatment-boosted anti-tafasitamab antibodies were observed. No clinically meaningful differences in the pharmacokinetics, efficacy, or safety profile of tafasitamab-cxix were observed in 2.5% of 81 patients with relapsed or refractory DLBCL with pre-existing anti-tafasitamab antibodies in L-MIND.

Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on MONJUVI use in pregnant women to evaluate for a drug-associated risk. Animal reproductive toxicity studies have not been conducted with tafasitamab-cxix. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. MONJUVI is administered in combination with lenalidomide for up to 12 cycles. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide prescribing information for additional information. Lenalidomide is only available through a REMS program. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G (IgG) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, MONJUVI may cause depletion of fetal CD19 positive immune cells. Defer administering live vaccines to neonates and infants exposed to tafasitamab-cxix in utero until a hematology evaluation is completed. Data Animal Data Animal reproductive studies have not been conducted with tafasitamab-cxix. Tafasitamab-cxix is an IgG antibody and thus has the potential to cross the placental barrier permitting direct fetal exposure and depleting fetal B lymphocytes.

8.2 Lactation Risk Summary There are no data on the presence of tafasitamab-cxix in human milk or the effects on the breastfed child or milk production. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to MONJUVI are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with MONJUVI and for at least 3 months after the last dose. Refer to lenalidomide prescribing information for additional information.

8.3 Females and Males of Reproductive Potential MONJUVI can cause fetal B-cell depletion when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Refer to the prescribing information for lenalidomide for pregnancy testing requirements prior to initiating the combination of MONJUVI with lenalidomide. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose. Additionally, refer to the lenalidomide prescribing information for additional recommendations for contraception. Males Refer to the lenalidomide prescribing information for recommendations.

8.4 Pediatric Use The safety and effectiveness of MONJUVI in pediatric patients have not been established.

8.5 Geriatric Use Among 81 patients who received MONJUVI and lenalidomide in L-MIND, 72% were 65 years and older, while 38% were 75 years and older. Clinical studies of MONJUVI did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs compared to that of younger subjects. Patients 65 years and older had more serious adverse reactions (57%) than younger patients (39%).

Tafasitamab-cxix is an Fc-modified monoclonal antibody that binds to CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Upon binding to CD19, tafasitamab-cxix mediates B-cell lysis through apoptosis and immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In studies conducted in vitro in DLBCL tumor cells, tafasitamab-cxix in combination with lenalidomide resulted in increased ADCC activity compared to tafasitamab-cxix or lenalidomide alone.